PVFS/ME/CFS Watch

Monday, November 22, 2004

Mary Anning clears the way for housework

Mary Anning (not the late great fossil hunter) writes about how a birthday gift from a friend turned into having to do a load of housework to get things out of the way for house cleaners (the gift) to be able to clean.

Recently, someone advised me that cleaners won't do any work that requires getting down on hands and knees. In order to get such jobs done, it seems you have to provide the right tools for each job.

In the case of a non-carpeted piece of flooring the size of a doormat, I'd have to supply a sponge mop on a stick with a bucket. I haven't worked out how skirting boards get washed.

Personally, I think the sign of someone who doesn't know how to clean, is one that refuses to see things from the eye level of a cat. It's amazing what you notice when you get that close up to corners, skirting and door edges especially in kitchens, bathrooms and hallways. Get down on your hands and knees and take a look - you'll be surprised.

Friday, November 12, 2004

'Toxin link' to Gulf War Syndrome

Some 6,000 Gulf veterans have suffered from various complaints. A report out today says Gulf War Syndrome is not stress related and not in the mind. It is actual physical damage caused by the chemicals that troops were exposed to. Here is a copy of the latest BBC report out today:

UK pressure groups have demanded ministers recognise Gulf War Syndrome as a genuine illness after a US report identified a link to toxin exposure.

A report by the Veterans Affairs Department claims thousands of British and US troops may have suffered from nerve gas exposure during the 1991 war.

The illnesses suffered by veterans are not explained by stress, it says.

The UK Ministry of Defence has always said there is not enough evidence to support the syndrome's existence.

The report, by the Research Advisory Committee on Gulf War Veterans' Illnesses, said up to 30% of US Gulf War veterans had been afflicted by a "complex of multiple chronic symptoms over and above expected rates seen in veterans who did not serve in the Gulf War".

It added that research had consistently found wartime stress and psychiatric illness did not explain Gulf War illnesses in the large majority of sick veterans.

It found veterans had developed Lou Gehrig's disease at about twice the rate of veterans who did not serve in the Gulf War.

Elizabeth Sigmund, of the Gulf Syndrome Study Group, praised the work done in the US.

She said: "The MoD has ignored all these things. They haven't done the sort of clinical research that has been carried out by scientists in the States.

'Not stress-related'

"What the Americans are saying is that the illness is not stress-related and not in the mind.

"It is actual physical damage caused by the chemicals that troops were exposed to."

Labour peer Lord Morris of Manchester, who helped establish the independent British inquiry into Gulf War illnesses under Lord Lloyd, welcomed the US findings.

He said: "This is a major development in unravelling the truth about the lessons of the still medically unexplained Gulf War illnesses.

"The advisory committee is to be congratulated in its frank exposure of the dangers to which the troops were exposed."
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Here is a copy of a November 04, 2004, report entitled "Gulf War Syndrome Cause Probably Found":

The New Scientist is reporting that after extensive studies by researchers at the Veterans Administration, the cause of Gulf War Syndrome has been possibly traced to exposure to Sarin gas.

According to leaks of a report, which is due to be released next week by the US Department of Veterans Affairs’ Research Advisory Committee on Gulf War Veterans’ Illnesses, "a substantial proportion of Gulf war veterans are ill with multisystem conditions not explained by wartime stress or psychiatric illness".

Some 30% of Gulf veterans suffer from various combinations of fatigue, muscle and joint pains, headache, and gut and cognitive problems – over and above non-Gulf veterans, the report says.

It blames damage caused by nerve gas and its antidotes, and organophosphate insecticides (OPs), which all block the enzyme that normally destroys acetylcholine, an important neural signalling chemical.

...

Haley’s work has allowed precisely that exploration. Syndrome 2, the worst of the three, correlates strongly with exposure to OPs and suspected exposure to the nerve gas sarin.

Furthermore, Haley’s team and two other groups have independently found specific neural damage that could explain some of the veterans’ symptoms. These veterans also had lower levels of the variant of an enzyme, paraoxonase, which breaks down sarin-like compounds.

The nerve gas link is crucial to the change of heart in the US. British and US authorities have denied there was any damage to troops as no soldiers showed the classic symptoms of acute exposure. But it now appears that very small, repeated exposure can also harm.

Experiments on animals have shown that exposure to doses of sarin too low to cause observable immediate effects causes delayed, long-term nerve and brain damage similar to that seen in veterans.
If true this would allow thousands of those exposed to claim pensions from the military and receive medical care. I'm not worried about the money, I just hope that we take care of our soldiers that were exposed to toxins while in a military operation.

Increased neutrophil apoptosis in chronic fatigue syndrome

"Evidence is emerging that people with chronic fatigue syndrome may have a detectable immunological abnormality. People with chronic fatigue syndrome often report symptoms consistent with an underlying viral illness, and increased neutrophil apoptosis (programmed cell death) is found in patients with infection. A study of 47 patients with chronic fatigue syndrome found they had higher numbers of apoptotic neutrophils and lower numbers of viable neutrophils than did 34 healthy controls. The cases also had increased expression of the death receptor on their neutrophils."
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Increased neutrophil apoptosis in chronic fatigue syndrome

Here is a copy of the Short Report Abstract in Journal of Clinical Pathology 2004 by G Kennedy, V Spence, C Underwood and J J F Belch:

ABSTRACTBackground/Aims: Many patients with chronic fatigue syndrome (CFS) have symptoms that are consistent with an underlying viral or toxic illness. Because increased neutrophil apoptosis occurs in patients with infection, this study examined whether this phenomenon also occurs in patients with CFS.

Methods: Apoptosis was assessed in patients with CFS in conjunction with concentrations of the anti-inflammatory cytokine, transforming growth factor ß1 (TGFß1).

Results: The 47 patients with CFS had higher numbers of apoptotic neutrophils, lower numbers of viable neutrophils, increased annexin V binding, and increased expression of the death receptor, tumour necrosis factor receptor-I, on their neutrophils than did the 34 healthy controls. Patients with CFS also had raised concentrations of active TGFß1 (p < 0.005).

Conclusions: These findings provide new evidence that patients with CFS have an underlying detectable abnormality in their immune cells.

Support: The study was funded by the charity ME Research Group for Education and support (MERGE — charity number 1080201), Perth, UK. Further support was also received from the Sir John Fisher Foundation (Educational Grant).

Introduction: Many patients with chronic fatigue syndrome (CFS) have symptoms that are consistent with an underlying viral or toxic illness. Considering that increased neutrophil apoptosis occurs in patients with infection, we examined whether patients with CFS also demonstrate increased numbers of neutrophils undergoing apoptosis.

Methods: Forty-seven patients (18 M & 29F, mean age 47.5 years [19-63 years]) who fulfilled the Centers for Disease Control classification for CFS were enrolled into the study. Thirty-four sex- and aged-matched healthy volunteers (13 M & 21F, 45.9 years [19-63 years]) were also recruited. The apoptotic process was measured isolating the neutrophils and incubating them with annexing V and or propidium iodide (PI) and by measuring leukocyte TNF-RI surface expression levels using a fluorescent-labeled antibody. An ELISA was used to measure platelet poor plasma levels of TGF-b1.

Conclusion: We have shown that patients with CFS also have increased neutrophil apoptosis and higher levels of TGF-b1. We suggest that increased neutrophil apoptosis and inhibition of transmigration of neutrophils by higher TGF-b1 levels may be indicative of a persistent viral infection or a toxic state giving rise to many of the symptoms which characterize CFS. It might also be that increased apoptosis merely reflects a quicker turnover of neutrophils in this condition, but either way the data presented here provides convincing evidence that many patients with CFS have an underlying detectable abnormality.

Comments: BMJ, 2004 August 21;329:468 and J Clin Pathol, including a response by the authors

Non-technical summary

Comment by MERGE: Some of the symptoms of ME/CFS are suggestive of an underlying viral or toxic illness associated with persistent infection and immune activation. Indeed, there have been various reports of immunological disturbances and viral infections in the illness [1]. Neutrophils represent 50-60% of the total circulating white blood cells, and are short-lived reactive cells fundamental to the functioning of an intact immune system. Minor alterations to neutrophil function can have profound immunological consequences, with amplification of the inflammatory response and the production of cytokines. As part of the resolution of inflammation, accumulated neutrophils are removed by apoptosis, a process where unwanted or damaged cells are eliminated without releasing their toxic contents and enhancing the inflammatory response. It is also a process associated with release of anti-inflammatory mediators, most specifically the production of transforming growth factor beta-1 (TGF beta-1), implicated in the pathogenesis of CFS.

While increased neutrophil apoptosis is present in patients with infection [2], this is the first time elements of neutrophil function have been determined in ME/CFS patients. The importance of these findings lies in the fact that neutrophils from ME/CFS patients have a greater proportion of apoptotic cells and are significantly less viable when compared with healthy subjects. The same neutrophils expressed a higher percentage of the death receptor TNF-RI and had increased binding of annexin V, indicative of phosphatidylserine exposure. Apoptosis is triggered by signals initiated by both external stimuli and internal sensors. The death receptor mediated pathway or the extrinsic pathway starts with the binding of TNF-family ligands to the death receptor TNF-RI, and results in a cascade of immune events. There is, however, crosstalk between the extrinsic and the intrinsic (mitochondrial-dependent) pathways which can result in the release of cytochrome C and the triggering of further apoptotic mechanisms These authors have demonstrated that ME/CFS patients have an increased neutrophil expression of TNF-RI, and surmise that the accelerated apoptosis of these cells is a consequence of extrinsic factors affecting apoptotic pathways. The additional finding that neutrophils from ME/CFS patients have more surface expression of TNF-RI further indicates that such cells are obviously more susceptible to apoptosis.

An increased rate of apoptosis of neutrophils may impact on the innate immune system of ME/CFS patients given that neutrophils are the major effector cells of this system. The decision for neutrophils to undergo accelerated apoptosis is a complex one and, in these patients, it may be a consequence of several factors. Accelerated apoptosis is indicative of a persistent or reactivating infection or a toxic state, reprogramming of apoptotic pathways by an infectious or toxic agent, or quicker neutrophil turnover, secondary to an abnormal host response to noxious stimuli.

With the advent of gene profiling, the search is on for causative agents in ME/CFS. In combination with previous reports of increased apoptosis in lymphocytes (rather than neutrophils) in these patients [3,4], the data presented by these authors is consistent with the presence of an underlying, detectable abnormality in the immune cell behaviour of ME/CFS patients, consistent with an activated inflammatory process.

Non-technical summaries of MERGE-sponsored projects

Standing up for M.E.

Copy in full of a report at MERGE by Dr Vance Spence and Prof Julian Stewart - Published in Biologist 2004; 51(2): 65-70

The Summer 2004 issue of Biologist (volume 51(2), pages 65-70) — the prestigious journal of the Institute of Biology, which is the professional body for 14,000 UK biologists— contains the article "Standing up for ME" by Dr Vance Spence (Chairman of MERGE & Senior Fellow in Medicine, University of Dundee, UK), and Prof. Julian M. Stewart (Professor of Pediatrics and Physiology, New York Medical College, USA).

This stimulating and authoritative review article — which begins with the plea, "Data, data everywhere and no one stops to think", examines the problems of orthostatic intolerance in "CFS/ME". One of the key difficulties that ME patients face is standing (orthostasis), particularly standing still. Inability to remain standing because of subjective findings (symptoms) or objective findings (signs such as hypotension) is designated "orthostatic intolerance". Many ME patients are unaware that something as simple as being upright can trigger a cluster of symptoms, such as dizziness, altered vision, nausea, fatigue, neurocognitive difficulties, headache, sweating and pallor. Orthostatic intolerance is characteristic of so many of these patients that it may very well serve as a definable subset in its own right, and might even be seen as diagnostic if the underlying mechanisms could be understood.

For copyright reasons at the Institute of Biology, the full text of this review article cannot be made available. However, some paper reprints are available, and can be obtained from MERGE (small donation welcome).

MERGE comment

This article looks at the various definitions of orthostatic intolerance and the differences between them. It also sets out to explain the specific mechanisms that might underly the problems that CFS/ME patients have when they are upright. Standing upright provokes major shifts of blood volume in the human body. Without compensatory mechanisms, the pooling of blood in the lower body and the position of the human head well above the heart would combine to produce unconsciousness in us all. In order to maintain blood pressure and consciousness, there are effective compensatory mechanisms.

The article makes clear that what happens in CFS/ME has little to do with cardiovascular deconditioning; indeed, the problems associated with the illness are most likely to be found in peripheral rather than central mechanisms, although a mixture of both may be applicable to some patients. Much has been written about orthostatic intolerance in CFS/ME but most of this is qualitative; i.e., patients have been subjected to tilt-table testing, most have positive results of one form or other, but very little research has addressed the mechanisms of the problems associated with being upright. Both authors have been studying circulatory problems in CFS/ME patients from different perspectives and this article brings these separate disciplines together.

The central question is what causes orthostatic intolerance in CFS/ME? It is clear that all of the problems cannot be explained by central or autonomic nervous system irregularities, but if CFS/ME is not autonomic dysfunction then what is it? A number of specific yet disparate mechanisms have evolved over time to explain orthostatic intolerance, but vascular dysfunction appears to be best supported by the available data.

CFS/ME patients with chronic orthostatic intolerance/postural tachycardia syndrome (POTS) often (but not always) display significant blue discolouration and sometimes swelling (pooling) of the legs, most especially on getting up in the morning. This suggests that vascular abnormalities form the basis for many of the findings of CFS/POTS and fit in well with our knowledge of compensatory mechanisms for orthostatic stress. This has been termed the vascular hypothesis, which includes possible autonomic dysfunction as a subset. Current thinking about both CFS/ME and POTS has emphasized the importance of disturbed blood flow physiology, and some investigators have grouped patients by their patterns of altered blood flow into three groups: "high flow", "low flow" and "normal flow" POTS.

It should also be borne in mind that the onset of orthostatic symptoms in many CFS/ME patients is often predated by a viral infection. The involvement of inflammatory cytokines such as IL-1, IL-6 and tumour necrosis factor, and nitric oxide (NO) needs to be considered. NO is an obvious candidate for generating orthostatic symptoms, and since there is clearly a problem with local vasodilator and vasoconstrictor mechanisms in these patients, an imbalance between endothelial and immunological-derived NO is an area worthy of further study. Of further interest are potential autoimmune mechanisms and the recent finding that circulating self-antibodies against nicotinic receptors interfere with neurotransmission in patients with problems of the autonomic nervous system, including orthostatic intolerance.

The article concludes that treatment of orthostatic intolerance in CFS/ME will not be possible until the mechanisms underlying the problem are unravelled and quantified. Of specific interest to MERGE is the role of endothelial-dependent vasodilatation and the various pathways surrounding acetylcholine sensitivity in CFS/ME patients. MERGE is currently funding a project examining the relative contributions of endothelial-derived hyperpolarising factor, prostacyclin and NO that are associated with acetylcholine vasodilatation in CFS/ME patients, and the first results of this new research study should be available sometime in 2005.

Severely Overlooked by Science — An Overview of Research on Severely-ill People with ME

The following is a copy in full of an article by MERGE and the 25% ME Group published at the website of ME Research Group UK (MERGE). A short version originally appeared in the August 2004 issue of the magazine InterAction.

Ignored and invisible! When the authors of the Chief Medical Officer's report of 2002 coined that phrase they were referring to the exclusion of the most severely ill people with ME from community and social care provision. However, the same description also holds true for mainstream scientific research.

A cursory glance at the existing scientific literature on ME (largely held in electronic databases — mainly MEDLINE — and specialist resources like the downloadable database of some 3000 abstracts at the MERGE website) reveals the virtual absence of information on the most severely affected people.

The Table below gives the number of articles (loosely defined) published for some randomly-chosen illnesses, and it shows two things. First, that ME is a Cinderella illness compared with other comparable chronic conditions in terms of volume of research publications; and second, that research on the severely ill is a rarity in most illnesses, including ME.

Table. Number of MEDLINE entries to May 2004 for a range of illnesses including ME/CFS. The percentage of these relating to severe illness (variously defined) is also shown. These crude ballpark figures illustrate well enough the paucity of research into ME/CFS, and on severely ill people in particular.

*In practice, very few of these studies deal specifically with the most severely ill people with ME/CFS (i.e., the housebound, bedbound or immobile).

The point is that severely affected people with ME are doubly disadvantaged: not only is this illness under-researched compared with other chronic conditions, but the most severely ill group of patients is under-represented in what little research is done. In fact, very few studies exist, and all define "severe illness" in different ways, complicating interpretation of the findings. And specific laboratory-based or experimental studies on severe sufferers are as rare as hens' teeth.

The findings so far...

For the record, the studies in question that present some kind of patient data (albeit with varying definitions of "severe" illness) include:

a) Effect of specialist hospital programmes — The CFS team at Oldchurch Hospital in Essex surveyed the 72 most severely affected CFS patients admitted 1990–98. They found that 46% had actually been discharged with an alternative diagnosis to CFS, that patients with a symptom duration greater than five years appeared to improve, and that the level of severity did not preclude improvement (Cox & Findlay, 2000). In a subsequent quasi-experimental study, this team found that their occupational therapy intervention significantly improved perception of health and "length of time tired" in patients compared with waiting list control patients (Cox, 2002).

The Oldchurch team have continued to audit the outcomes of their work, and the most recent of these (December 2003) examines 24 severely affected patients following an inpatient stay. While two-thirds saw their severity rating improve by one or two grades, on a scale of one to five, a third saw no change in their level of severity. However, 50% reported a positive shift in mood and 87% described an increase in their quality of life post-admission. Using a patient feedback questionnaire, 39% rated their satisfaction with the CFS service as 10/10, with just 4% giving a score of less than five.

Two similar, smaller outcome studies (Chalder et al, 1996; Essame et al, 1998) also reported appropriate multidisciplinary inpatient rehabilitation to be beneficial, at least in terms of "functional ability", to the majority of severely affected patients. (Five out of six patients "functionally improved" in the Chalder study and 17 out of the 19 followed up in the Essame study).

b) An experimental study of cardiac output — Researchers examining 38 patients found that participants with "severe" CFS had significantly lower cardiac output than the controls and less ill patients (Peckerman et al, 2003). Post-exertional fatigue and flu-like symptoms of infection clearly differentiated the patients with severe CFS from those with a less severe presentation, and were predictive of lower cardiac output. These results, say the researchers, "provide a preliminary indication of reduced circulation in patients with severe CFS".

c) Investigating longer-term outcomes — One study has evaluated the natural history of CFS in a severely ill group of 24 patients at three points in time (Hill et al, 1999). Over the four years of the study, thirteen patients remained severely ill, nine improved but still fulfilled the 1994 case definition for CFS, and one recovered. Illness duration, mode of onset, psychiatric status/depressed mood at intake, or chemical sensitivity did not appear to predict illness outcome. Not surprisingly, mood improved for those patients whose illness lessened. The researchers concluded that the prognosis for full recovery was extremely poor for the most severely ill subset of CFS patients.

Another outcome study of severely affected children (Rangel et al, 2000) followed up 25 children using child-parent interviews. After nearly four years, two-thirds of the children had recovered, and none had developed any other medical conditions, allowing tentative conclusions that severe illness can cause severe handicap but that most children recover.

In addition, one report has detailed outcomes for two wheelchair-bound CFS patients treated by a "pragmatic intervention" consisting of more than 50 face-to-face or telephone contacts with a therapist over approximately two years. By the end of the intervention, both patients were reported to be free of their wheelchairs and leading "relatively independent existences" (Powell et al, 1999). And two reports have also been published giving results from the Case History Research On Myalgic Encephalomyelitis (CHROME) database (Gibbons et al, 1996 & 1998).

Why is there so little research?

The CMO report defined the severely affected as those "patients whose physical disability is most severe, leading to serious restrictions in mobility and functioning. In many, these restrictions are accompanied by other markers of severity, such as cognitive impairment or prolonged course" (Section 3.4.3). Clearly, anyone who is severely affected would struggle to attend hospital-based investigations, which often require multiple visits.

However, even if they could attend, they might well be excluded for other reasons, such as the presence of "co-morbid" illnesses which often accompany severe ME and its consequences (e.g., long term immobility with accompanying deconditioning, susceptibility to infection, etc.), or their inability to fulfill the requirements of a trial (e.g., perform graded exercise or stop current medications). Sensible though these restrictions might seem to healthy young researchers, they are little comfort to severely ill people who wish to see scientific progress within their own lifetime! Of course, it is feasible to conduct a "pragmatic" study in which a "treatment" is given to a large group of diverse patients in their own homes, and one of these — the FINE trial — has just begun.

The FINE Trial — thanks a £million?

Heralded as offering a "promising new treatment" for people with severe ME, the FINE (Fatigue Intervention by Nurses Evaluation) Trial is presently recruiting staff and will report its conclusions in 2008 or even later. Costing £1,147,000, the trial is funded by the UK's Medical Research Council with a grant to Dr Alison Wearden, a psychologist based in the Department of Psychology, University of Manchester, and colleagues in Liverpool (Department of Psychiatry) and Manchester (Department of Psychiatry). In the preliminary supporting documentation, the FINE Trial is a described as a "randomised controlled trial of nurse-led, self-help treatment for patients in primary care... Referred patients will be randomly allocated to one of three treatment groups: (a) nurse-led self-help, (b) supportive listening or (c) GP treatment as usual." Patients will be visited in their own homes, and before "treatment" commences qualitative interviews will be conducted to explore"patient views on illness causation, beliefs about chronic fatigue, expectations of intervention, and previous experience of treatment and doctor-patient relationships". At the same time, the patients' GPs will be asked about their experiences of and attitudes towards patients with ME. After 20 weeks of "treatment", patients will be assessed for a variety of outcomes, and again after one year.

What is the "promising new treatment" on offer to the severely-ill patients? Called "nurse-led self-help" or "pragmatic rehabilitation", the approach "is designed to increase activity and challenge dysfunctional illness beliefs" (Powell et al, 1999), and includes elements of the cognitive behavioural and graded exercise therapy championed by those psychiatrists and psychologists who promote the "biopsychosocial" model of ME. The basis of this model is that "once an illness has started, its expression is affected by beliefs, coping styles, and behaviours, while consequential physiological and psychological effects act in some ways to maintain and/or modify the disease process" (CMO Report 2002). Pragmatic rehabilitation, we are told, will help patients to understand their symptoms and, jointly with the nurse, agree a programme of rehabilitation. In support of its usefulness for the most severely ill patients, a single report in the scientific literature (Powell et al, 1999) describes two wheelchair-bound patients who had dramatic improvements in health following the pragmatic rehabilitation regimen now being rolled out to larger groups of patients as a full-scale MRC-funded trial. (Two other seemingly relevant reports in the scientific literature are, in fact, small pilot studies that refer to inpatient treatments within psychiatric wards, vis, Chalder et al 1996 and Essame et al 1998.)

This treatment is not new and hardly promising on the basis of two case reports. But will some people benefit and report improvement of a sort? Well, probably — given that the quality of life of us all (well or unwell) can be improved by changing some of our beliefs and coping behaviour, and increasing our activity levels. But as the authors of the new Canadian definition of CFS/ME make clear, the question is whether such treatments (generally recognised not to be a cure for patients' physical illnesses or suitable for everyone with ME) add anything to what is available in the general medical setting, and hence whether the taxpayer-spend of £1,147,000 (including £411,000 in NHS costs, very useful for oiling the wheels of academic departments) is value for money. And furthermore, there are considerable doubts about whether the trial will address the central problem of ME.

For instance, will each severely-ill person on the FINE trial be given a comprehensive medical assessment to identify somatic (physical) symptoms and signs? Autonomic disturbances, seizures, frank muscle weakness, neuroendocrine disturbances (like sweating episodes), recurrent flu-like symptoms — will they be recorded over the 70 weeks? Symptoms like musculoskeletal pain, neurocognitive problems and sleep dysfunction — will they be comprehensively assessed? Will patients receive treatment for any of these? Or will these signs and symptoms of ME be ignored while the patients' beliefs are explored by nurses steeped in the biopsychosocial culture of their paymasters? Because the full protocol for this trial has not been made publicly available, despite being publicly funded, it is impossible to know...

But one thing we do know. The FINE trial is recorded under the "Mental Health in Primary Care" programme in the National Research Register 2004. And there's the rub. Given the expanding core of evidence for a biological pathology for this illness, it is widely felt by patients, support groups and their political representatives that scarce research funding would be better targeted at appropriate biomedical investigation and treatment of the physical basis of ME.

A scandalous situation overall

As regards biomedical research overall, there is a serious mismatch between published studies and the extent of the human problem. While we know very little about the incidence and prevalence of ME generally, the proportion of patients with severe illness has been variously estimated at 25% (hence, the "25% ME Group for Severe Sufferers"), one third who experience "a severe and debilitating downhill course" (Dr Melvin Ramsay), and 34% as reported by Action for ME's Members Survey of November 2000. This evidence, conjoined with findings from the CMO's report that "a minority... remain permanently, severely disabled and dependent on others", illustrates the scale of the problem that still needs to be addressed.

To put it bluntly, if 30% of ME patients in the UK are severely affected at any one time, this means that between 36,000 and 72,000 people are severely ill. For such numbers to be so under-investigated by scientists, albeit for practical reasons, is surely scandalous — yet this is the situation. The CMO's Report concludes that "Current provision of services falls well below what is needed for the vast majority of severely and very severely affected patients" (Section 3.4.3.1).

Stabbing in the dark

It's sobering to consider that in 2004 we still understand very little about the origin and outcome of severe illness in ME. Yes, we know that severe illness (and the other medical conditions that accompany it) complicates matters. We know that the prospects for recovery tend to be worse for those most severely affected, whether adults or children, and that specific viral triggers, duration of illness and socioeconomic status have all been associated with the severity of the clinical picture. Most importantly, we know that the cumulative impact of severe illness over many years, where there is no sense of improvement, is profound.

Yet, even these rather unsurprising findings are based on a relatively small number of investigations, and as such cannot be called definitive. The truth is that, after some stabbing in the dark, the complexity, severity and longevity of the illness are still only dimly perceived. The most meaningful information often comes from the dedicated efforts of specialist groups that have collected data on their severely ill members or clients (see the box below).

25% ME Group for Severe Sufferers — Severely affected analysis report, March 2004 • Community care provision either non-existent or inadequate
• Most patients unable to attend GP, yet minority get GP home visit
• Unhelpful psychological strategies, e.g., cognitive behavioural therapy (93% unhelpful) and psychotherapy (90% unhelpful)
• Worsening of condition with graded exercise therapy (tried by 39% of members, and 82% made worse by it)
• More than half waited longer than two years for formal diagnosis

Action for ME Report — Severely Neglected: ME in the UK, March 2001 • 41% reported having been bedbound now or in the past
• More than half reported to have felt suicidal because of their illness (especially those with severe pain and late diagnosis)
• 80% suffered severe pain as a result of their illness
• 15% had more than one close family member who had also had ME

Case History Research on Myalgic Encephalomyelitis (CHROME) • Database providing ongoing monitoring and progress of adults and children severely affected by ME via regular questionnaires

Soft data and hard experience

Clearly, community-based surveys can be very useful for describing the experiences of people with severe ME, and might be important for hypothesis generation; i.e., they may uncover areas of concern (such as the lack of community care provision), and highlight areas where new research is needed (such as the urgent need for pain relief). In short, they can provide a systematic record of individual suffering, and point to ways to alleviate it.

However, there is a very real problem about the meaning of survey data generally to medical/scientific professionals outside of ME patient circles. Strange as it may seem, surveys come low (grade III or lower) in the hierarchy of research designs, since they are not valuable for determining causation, or the "specific effect" of treatment.
In addition, charities' "in-house" patient surveys have many limitations. First, most of the data has usually not been collected using validated, standardised outcome questionnaires that can be used for comparison with other studies or illnesses. Then there is the problem of poor response rates that range from 66% down to 31% in recent ME group surveys, raising the whole question of the meaning of non-responses, a statistical minefield (fortunately) beyond the scope of this article.

But the greatest flaw in the eyes of suspicious outsiders is the "Christine Keeler" effect — "they would say that, wouldn't they". Since the survey data emanates from a so-called self-selecting group of people with self-reported symptoms, a question mark hangs over the veracity of the data, especially if — as some psychosocial professionals maintain — claiming to be severely ill can help maintain a sickness role and acquire state benefits.

A good example of the difficulties of getting such information published came in 2002 when the 25% ME Group and MERGE tried to publish a small table of data as a letter in the Journal of the American Medical Association. To say there was a lack of interest is an understatement: in the end, the data was presented in MERGE's report Unhelpful Counsel, and so was seen by — at most — a few hundred people instead of the 200,000+ members of the American Medical Association, the sort of audience the most severely affected patients, and the data, deserved. These problems with survey data are not specific to ME, by the way, but this illness — with its peculiar combination of public scepticism and professional uncertainty or outright distain — is probably more at risk than most.

Preparing to climb the mountain

Given that surveys are things that patient charities are well-positioned to undertake, there are in fact some simple things that groups representing the severely ill can do to facilitate the acquisition of valid information. One is to include with their custom-designed questionnaires at least one recognised validated outcome measure, such as the Medical Outcomes Study SF36, a short, easily-completed measure of quality of life that allows direct comparison with other illnesses and other types of ME patients. Again, groups could be willing to supply data for analysis by independent organisations though, of course, the ideal situation is for a university department or other professional group to be involved from the outset.

However, a most useful advance would be a national epidemiological investigation of the true prevalence and impact of severe ME. Indeed, as the CMO report made clear, the organisation of primary care services in the UK offers a unique opportunity to undertake prevalence studies on the national scale needed to generate the requisite data.

To end where we began, the same report stated in 2002 that "care of people who are severely affected is an urgent challenge". Scientific investigation of the severely affected — their clinical status, experience of illness and treatment — is also a challenge that should be swiftly met.

Ignored and invisible, maybe — but it doesn’t have to be like that. Energy, vision and funding can transform any situation.

Cortisol: The "Stress Hormone"

One day, when I am feeling a little stronger, I'll contact my GP and ask for a referral to a specialist - probably a neurologist or endocrinologist, or both. If by next year I don't feel improved enough to go out, I am mentally preparing myself for a stay in hospital to undergo the tests. At the moment, I just cannot organise or make the round trip journey, and all that is involved with visiting a specialist, including follow ups.

Some four and a half years ago, after reading a book on M.E. (by Dr Charles Shepherd), I asked a GP about Cortisol. He wasn't the right person to ask. He was a medical examiner on behalf of the government who came to my home assess my application to the department of works and pensions for disability living allowance. Doctors from government (or insurance company) medical boards have a reputation for seeking to dispprove claims. It was only afterwards I found out, one should always have a witness sit in on these horribly gruelling interviews.

Those were the early days of my illness. Now when I look back at what I had to endure, I shudder. After an hour and a half of answering his questions and watching him scribble my answers on 25 pages of a form, he asked me to sign the box where he'd summarised the exam. He read it out to me, insisted I sign it and refused to show me the other 24 pages. He said it wasn't necessary (I found out this is not true). I've never signed anything that I haven't at least glanced over but I was too ill to object and could barely see straight. When he left, I recall him saying he couldn't be sure what they'd make of his report.

My application was turned down. To cut a long story short, it went to Tribunal. Only then did I see what he'd written.
His shockingly weird spidery handwriting - one inch high - with an extreme slant to the right (and left) like one long series of heavy handed slashes, had to be seen to be believed. I'd never seen anything like it, except in books on handwriting analysis that gave such examples from people who had mental health or alcohol problems.

To my horror, I found out from an Advisor that my application was turned down probably because nobody could read the doctor's report, apart from a few lines he'd scrawled at the top of the front page that made judgements about my personality and character, described my home as "sparkling squeaky clean", said "everything was white" (not true - some colours were muted - even the carpets were dark, upholstery and bedcover were multi coloured tapestry quilt) - and that I was "dressed immaculately in snow white sweater and trousers" - he added that he "had to use a chair to lean notes on, instead of a table".

This was from a man who wore pale grey shiny fake leather slip-on shoes with dark brown polyester trousers. When I asked what he knew about M.E., he told me (in a derogatory tone) that he had seen "loads" of ME patients and that, quote "they all see in grey - if you turn them over you find they're all soft bellied." Charming eh?

A year later, after attending a Tribunal, I was awarded the disability living allowance, backdated to the date of my original claim. That one doctor caused me much distress and suffering and no doubt contributed towards my downward spiral because I couldn't get help for the first eighteen months of near total incapacity. Oh yes, and his answer to my question about Cortisol? He said "Ahhhh ... how interesting, you've picked up on that ... now, let me see .... I'll just make a note of this ... "well educated". I said if there is something wrong with ones Cortisol - is there a treatment to calm whatever is wrong - "oooh no" he said ... and mumbled something about adrenaline and heart attacks ... his answer was woolly but left me in no doubt that there was no treatment for Coristol problems (which is the reason I dropped the idea of asking for a test).

Fellow blogger Hazy, who has been very ill for the past year and is 80% housebound has undergone either doctors visits or tests every fortnight for the past 15 months. The tests rule out this and that. Still no firm diagnosis. Next appointment is with a gland doctor. Interestingly, Hazy is having Cortisol tests. She has explained in her blog that it can be done by 24 hour urine or blood tests. Urine tests can be done at home but blood tests require overnight stay in hospital. I look forward with interest to see what Hazy's Dr Gland says.

The following information that explains the stress hormone cortisol is courtesy of Melissa C. Stöppler, M.D. at
http://stress.about.com/cs/cortisol/a/aa012901.htm

Cortisol is a hormone which is secreted by the body in response to emotional and physical stress. Since cortisol levels rise rapidly in response to physical or emotional stresses, this hormone has been called the "stress hormone". Cortisol can be detected at any time in the body, and high levels of this hormone do not necessarily lead to stress.

This critical hormone is released in response to stress.

The hormone cortisol, which is released in the body during stressed or agitated states, has gained widespread attention as the so-called "stress hormone." But this hormone is more than a simple marker of stress levels- it is necessary for the functioning of almost every part of the body. Excesses or deficiencies of this crucial hormone are also lead to various physical symptoms and disease states.

Background

Cortisol is a steroid hormone made in the adrenal glands, which are small glands adjacent to the kidneys. Among its important functions in the body include roles in the regulation of blood pressure and cardiovascular function as well as regulation of the body's use of proteins, carbohydrates, and fats.

Cortisol secretion increases in response to any stress in the body, whether physical (such as illness, trauma, surgery, or temperature extremes) or psychological. When cortisol is secreted, it causes a breakdown of muscle protein, leading to release of amino acids (the "building blocks" of protein) into the bloodstream. These amino acids are then used by the liver to synthesize glucose for energy, in a process called gluconeogenesis. This process raises the blood sugar level so the brain will have more glucose for energy. At the same time the other tissues of the body decrease their use of glucose as fuel. Cortisol also leads to the release of so-called fatty acids, an energy source from fat cells, for use by the muscles. Taken together, these energy-directing processes prepare the individual to deal with stressors and ensure that the brain receives adequate energy sources.

The body possesses an elaborate feedback system for controlling cortisol secretion and regulating the amount of cortisol in the bloodstream. The pituitary gland, a small gland at the base of the brain, makes and secretes a hormone known as adrenocorticotrophin, or ACTH. Secretion of ACTH signals the adrenal glands to increase cortisol production and secretion. The pituitary, in turn, receives signals from the hypothalamus of the brain in the form of the hormone CRH, or corticotropin-releasing hormone, which signals the pituitary to release ACTH. Almost immediately after a stressful event, the levels of the regulatory hormones ACTH and CRH increase, causing an immediate rise in cortisol levels. When cortisol is present in adequate (or excess) amounts, a negative feedback system operates on the pituitary gland and hypothalamus which alerts these areas to reduce the output of ACTH and CRH, respectively, in order to reduce cortisol secretion when adequate levels are present.

Measurement of Cortisol Levels

The body's level of cortisol in the bloodstream displays what is known as a diurnal variation - that is, normal concentrations of cortisol vary throughout a 24-hour period. Cortisol levels in normal individuals are highest in the early morning at around 6-8 am and are lowest around midnight.

Normal levels of cortisol in the bloodstream range from 6-23 mcg/dl (micrograms per deciliter).

In addition to early morning, cortisol levels may be somewhat higher after meals. While the most common test is measurement of the cortisol level in the blood, some doctors measure cortisol through a saliva sample, as salivary cortisol levels have been shown to be an index of blood cortisol levels. Sometimes by-products of cortisol metabolism are also measured, such as 17-hydroxycorticosteroids, which are inactive products of cortisol breakdown in the liver. In some cases measurement of urinary cortisol levels is of value. For this test, urine is collected over a 24-hour period and analyzed.

Certain drugs can lead to increased cortisol levels. Examples include the diuretic spironolactone and estrogen hormone therapy. Low cortisol levels can be due to drug therapy with androgens or the anti-seizure medication phenytoin. Highly-trained athletes can have higher-than-average cortisol levels, and women in the last trimester of pregnancy also generally have elevated cortisol levels. Recent research has even shown that drinking 2-3 cups of coffee per day can elevate cortisol levels. Likely due to the increased physical and psychological stresses associated with these conditions, persons suffering from depression, anxiety, panic disorder, malnutrition and alcohol abuse also often have elevated cortisol values. Rare tumors of the adrenal glands or pituitary gland can also lead to abnormally high levels of cortisol.

Cushing's Syndrome

Persons exposed to abnormally high levels of cortisol over time develop a syndrome known as Cushing's Syndrome.

This condition generally affects adults, and approximately 10-15 per million persons will develop this condition each year. Signs and symptoms of Cushing's Syndrome include elevated blood pressure, development of diabetes, pink-to-purple stretch marks on the abdominal skin, fatigue, depression, moodiness, and accentuated fatty tissue on the face and upper back. Women with Cushing's Syndrome often have irregular menstrual periods and develop new facial hair growth. Men may show a decrease in sex drive. Treatment options are varied and depend on the cause of the excess cortisol.

Addison's Disease

Primary problems with the adrenal glands or with the pituitary gland can lead to a condition known as Addison's Disease, in which the adrenal glands fail to produce adequate amounts of cortisol. This condition occurs in persons of all ages and affects approximately one in 100,000 people per year. Symptoms are fatigue, low blood pressure, weight loss, weakness, loss of appetite, moodiness, nausea, vomiting, and diarrhea. The production of other hormones by the adrenal is also often affected, with reduced levels of the hormone aldosterone, which is important for body salt and water balance, often accompanying the reduction in cortisol. This condition can be treated by the administration of synthetic steroid hormone preparations.

Tuesday, November 09, 2004

A medical blog post on M.E. says being "tired" might be a disease!

Here below is a copy of one of the posts written by John Mastrangelo. It is dated November 7, 2004, and features M.E. Note my reply in comment number five.

[btw several weeks ago, Nick kindly published a post on Lyme disease, a subject that I plan to write about here - one of these days]

Being "tired" might be a disease!

Chronic fatigue syndrome, also known as myalgic encephalomyelitis, is an incapacitating illness that is estimated to affect between 400,000 and 800,000 Americans. It is a disease defined by symptoms and disability, with no known pathophysiology or confirmatory laboratory values. It seems that some physicians don't think it exists, while others are firm believers that it's a real entity. I've noticed different reactions to chronic fatigue syndrome from physicians and wanted to know what research was available on the subject.

Obviously, this disease is troubling to physicians because of it's indistinct nature, as well as it's economic impact on the US healthcare system. One study estimated it's impact to be 9.1 billion dollars. Another study recognized the difficulty of the diagnosis and tried to come up with standard measures of the disease. It was very interesting that one study delved into whether or not physicians actually believed CFS as a diagnosis. The study went on to recognize perception as a barrier in the treatment of the disorder.

Another study found several differences in their patient population with CFS. Increased body temperature, pulse, and evidence of deconditioning were all apparent. In any event, with respect to CFS, I would caution the health care community to take this entity seriously and to push for further research into it's etiology. To simply exclude CFS as a possibility because of a disbelief of its existence is not fair to one's patients or profession.

Posted By : John Mastrangelo | Link | Rotation 2 | Comments (5)

Comments: Being "tired" might be a disease!

I agree with you. Just because we don't understand something doesn't mean we should dismiss it. I wonder if depression plays a role in CFS.

Posted By Gazelle Aram / Posted At 11/7/04 9:44 PM

I did a little reading of my own on the subject, and it seems to me to be a real entity, and linked to depression. I think all psych related diseases are hard to understand because it is hard to measure anything.

Posted By Jeffrey Klauser / Posted At 11/8/04 9:21 AM

this seems to be like the debate over fibromyalgia - people either believe in it or they don't. i agree with jeff that psych-related disease are heard to understand, but with more and more treatment options to try, we should take people's complaints seriously and see what might work with them.

Posted By Rajanya Shah / Posted At 11/8/04 8:14 PM

thanks john. i liked the articles you linked. this is something i have a hard time getting my mind around.

Posted By Jonathan Cahill / Posted At 11/8/04 8:21 PM

Thank you for kindly highlighting the terrible ignorance and misunderstanding of this dreadful illness.

ME (aka CFIDS in the US) is recognised by the World Health Organisation as a neurological illness - not psychological.

Here is a link to MERGE that provides up to date information: http://www.meresearch.org.uk/melibrary/information/index.html

I have been severely affected by M.E. ever since I had a viral illness in October 1999. Here is a link to my story that I wrote in 2003: http://meandophelia.blogspot.com/2003/07/me-and-ophelia-is-personal-blog-of.html

Since that date, nothing much has changed. The changes that have taken place are that my condition has worsened but I have found ways to manage the pain and other symptoms through strict self dicipline and pacing. I've been housebound now since March 2003 and am horizontal 23.5 hours a day - without exception.

A year and a half ago, an NHS consultant from the ME Clinic here in England assessed my baseline as 15 minutes. If I live within my baseline and don't stand, walk or do any physical exercise for longer than fifteen minutes a day and avoid stress, I can manage to keep the pain and other symptoms at a more bearable level.

Going by the comments here, none of you have come across someone who is severely affected by M.E. Some are affected mildly - others moderately - it's estimated 25% are affected severely.

We are invisible. You don't see us out and about or talked about much. We have been excluded from research, treatment trials, experiments, tests, surveys etc., simply because we are too ill and too difficult to include. Over the past year or so this is slowly changing though. MS was taken seriously by the public when severely affected sufferers made themselves less invisible and came out in their wheelchairs. It will probably take another decade or two for people to take ME just as seriously.

I believe my experience proves that ME - like MS - is progressive. I've not yet come across a severely affect ME sufferer who has recovered. Those that I know have been ill for ten or more years - in some cases well over 20 years.

The comments written here are the sort of thing we are used to hearing from family, friends, colleagues and many in the medical and health care profession.

Such lack of understanding make this illness especially unbearable. There is so little compassion, people's attitudes feel cold and cruel - especially when it comes from the medical and health care profession.

The quality of life for someone like myself is the same as those suffering end stage AIDS.

All days for me are bad - some days, weeks and months are worse. A good day is a bad day. A bad day is one that is worse than the bad days.

If any of you who have commented here are a doctor and I presented myself as your patient - and told you my story, what would you say to me?

The reason why ignorance and misunderstandings are so damaging (and cruel and dangerous to us) is that treatment for psychological illnesses are the complete opposite of what's needed for ME sufferers. The activity involved in psychological treatments such as cognitive behaviour therapy and graded exercises can make the condition worse.

ME has been documented for at least 70 years. Plenty is known about it. Many doctors just don't care enough to read up on it.

Like in other walks of life, people are people - some are good at their jobs, others are not. Doctors are no different. If there are student doctors reading this, I feel 100% sure they will come across a case of ME -- and a severe case. Hopefully, by my taking time to write my story and commenting here, it will prove of benefit to future patients. I would be willing to answer any questions. Please feel free to contact me anytime. I am always here.

PS Recently I started a special blog for my posts on ME. It can be found at http://abreathofhope.blogspot.com

Another case history of a severely affected ME sufferer can be found in the first post. Please be sure to read it. It gives an accurate picture of this illness. Thank you, once again, for your kind attention.

Posted By Ingrid / Posted At 11/9/04 12:02 PM
- - -

Postscript: Before I forget, I meant to mention that the NHS Consultant from the ME Clinic assessed my baseline as 15 minutes and said after 20-30 minutes of mental activity to totally rest for five minutes at least. This I find is impossible to do. One cannot live any kind of life looking at the clock every half hour - or having an alarm go off - and having to reset it - it is too nerve racking. One may argue that it is better to try anything than be ill. I am bravely admitting here that it is impossible to carry out in reality. One would need a daytime nurse 12 hours round the clock to set a timer 24 times a day and physically tell one (like me) to switch off the laptop every half hour. I've been looking for an alarm clock for my laptop that might switch it off every 30 minutes - or show an alert of some kind, but I've not yet found it. The reason half an hour is so impractical is because it takes me so long to do one thing - a post on a good day might take me all day to write - not because my fingers are slow in typing (they are not) it's because of the slowness of concentration - takes hours to make a long piece short. On a bad day I cannot post at all.

Monday, November 08, 2004

BIOMEDICAL RESEARCH MAKES HEADLINES ON ME/CFS

Here below is an excerpt from an article in InterAction magazine that sounds promising. The magazine, received today, is published by UK patient charity Action for M.E., of which I am a member.

Although I do not know the meaning of the words "elevated levels of the cytokine interleukin-6", they SOUND to me like they might describe the poisonous "stuff" that flows around my veins like battery acid when I get stressed or over exert. Over exertion in my case means being vertical - even sitting up - for longer than 5 minutes.

Before reading this article, I'd tentatively pinpointed the stress hormone Cortisol as being one of the culprits (along with lactic acid) only because it's clear to me that my condition worsens considerably at the first sign of positive or negative (i.e. happy or unhappy) stress. Something is causing orthostatic intolerance. It's been said this could be caused by "sticky blood" which I find hard to believe because I've had loads of blood tests and as far as I know nothing untoward (except a virus in the initial fortnight of illness) has been found.

I've read of ME/CFS patients who have undergone tilt table tests. I find this particularly interesting because of an unusual sensation I experienced when visiting the dentist a few years ago. I was seated in a super modern dental chair that curved into a gentle "S" shape and the dentist pressed a button to turn the seat into a bed - and just as it was reaching a certain position, I felt a split second of well being, like something was released within my body that actually gave me such a sensation of wellbeing that I wanted to shout "eureka". It was such a fleeting moment but because of the journey getting to the dentist, my brain had slowed up and I did not have the presence of mind or energy to explain to the dentist what had just happened. I recall saying though, when I was leaving - "I love that chair of yours - wish I could take it home with me".

P.S. That dental appointment was in March 2003 and even though I had an adrenaline free injection, it finished me off. After the half hour appointment, I was so pleased to be out and about (I think I'd been almost bedbound for 3 months prior) that a friend and I got carried away browsing for more than an hour in nearby shops. On the way home in the car, we stopped off at a farm shop to buy deli treats. In the farm shop, I felt so ill and confused I hardly knew what I was doing. Could barely see straight, couldn't concentrate and had to ask the shopkeeper to switch off the music playing on the radio. It took every fibre of my being to stand up - but I didn't have the presence of mind to sit down either. It's a most horrible experience that is difficult to describe. I remember feeling very, very cold and yet hot at the same time. Feverish. On the journey home, I found great difficulty in sitting up in the passenger seat. It felt like my skeleton and innards were screaming out red alarm bells and turning to mush inside my body. My body felt it was being held up by a structure that was collapsing internally. Since that date, it's turned out that I've lost my mobility and have not been outdoors beyond my front gate ever since. I'm still not able to be vertical for longer than ten minutes without it affecting my faculties (but not my intellect). Five minutes is OK. My daily baseline for anything other than laying on the couch with the laptop is fifteen minutes. I can do something once - ie fetch the mail down several steps - go back up again. But I cannot repeat it without at least a days rest.

Here is a copy of the article "Biomedical research makes headlines":

The British Medical Journal (BMJ) ran a short piece acknowledging a recent study undertaken by research charity MERGE. Stating that:

"Evidence is emerging that people with CFS may have a detectable immunological abnormality", the article quoted the study's finding that a greater number of white blood cells die early in CFS compared to healthy controls. Even Dr Hilary Jones in the News of the World picked up on the discovery, explaining that this problem can weaken the immune system and cause symptoms of chronic fatigue.

Another piece of biomedical research covered extensively by newspapers has suggested that elevated levels of the cytokine interleukin-6 could be one cause of CFS. The study, carried out on athletes, showed that fatigue levels , leg pain, mood and performance were worse after they were given a dose of this cytokine (a chemical produced by the body during infection).

Dr Robson-Ansley wrote in GP magazine that: "Chronic stress seems to change receptor expression, making people more sensitive to interleukin-6." In The Times, she went further: "It is hoped that a drug which blocks the IL-6 receptor in the brain, currently in clinical trials, could help relieve CFS, which is often difficult to treat." Watch this space!

Finally, The Times and BBC Online covered a study by Viner and Hotopf published in the BMJ this October dispelling myths about who gets ME. In terms of childhood markers, researchers found no link between ME/CFS and psychological problems of mothers, children or adolescents. However the study found a link between previous long-standing medical conditions, sedentary lifestyles and subsequent onset of the illness.